Food acquisition and reproduc-tion wood and collard

University, Washington, DC 20052

KEY WORDS body size; hormones; IGF; evolution

BODY SIZE AND THE ‘‘BIG PICTURE’’

Body size in nonhuman primate and human

Living mammals span an impressive range of body size, as do living primates (Smith and Jungers, 1997). The range of body size encompassed by fossil primate taxa is even greater than that among extant groups. Debate regarding the body size of the ancestral primate is ongoing. One group of scholars argues that based on the available fossil evidence and the adaptations that would have occurred before the early Eocene radiations, the ancestral primate would have been very small, per-haps less than 50 g (e.g., Gebo, 2004). Another group suggests that an increase to 1 kg or more in the primate stem lineage led to the reduction of claws to nails (e.g., Soligo and Martin, 2006). There seems to be a consensus that the earliest anthropoids were small-bodied, with supporting evidence from some very small stem anthro-poid fossils (e.g., Ross, 2000; Williams et al., 2010). Mul-tiple primate radiations have clearly been characterized by extremes in size (e.g., platyrrhines, Ford and Davis, 1992; lemurs, Godfrey et al., 1990; cercopithecines, Del-son et al., 2000). Sexual dimorphism in body size is com-mon among anthropoids (Plavcan, 2001), and intraspe-cific variation in body size among primate species has

*Correspondence to: Robin M. Bernstein, Department of Anthro-pology, Center for the Advanced Study of Hominid Paleobiology, The George Washington University, Washington, DC 20052.

phylogeny (e.g., Plavcan and van Schaik, 1997). Life his-

tory profiles of primates are likely to have evolved both through grade shifts that were body mass dependent and shifts that took place independently of changes in mass (Kelley and Smith, 2003; Marroig and Cheverud, 2005).

It has often been argued that the main forces that exert pressure for the evolution of larger size are fecun-dity selection (for females) and sexual selection (for

The rules. There are a number of general evolutionary trends observable in body size throughout various organ-ismal forms. These include Cope’s rule (e.g., phyletic size increase), which states that taxa tend to evolve larger body sizes over evolutionary time, because of the advan-tages conferred by large size, including the ability to bet-ter withstand short-term fluctuations in the environment and the capability to exploit a broader range of low-qual-ity resources (Maurer et al., 1992). This has been explained by some as representing not true evolutionary trends in size, but rather differential preservation in the fossil record, biased toward larger forms. Stanley’s rule explains Cope’s rule as a statistical generalization and also states that clades tend to originate at small body sizes, thereby giving rise to a pattern of size increase dur-ing radiation (Gillman, 2007). It has been suggested that although plesiadapiforms (variably attributed as either the extinct sister group or precursor of primates) followed an overall trend of increasing body size with evolutionary time and, therefore, conformed to Cope’s rule, primates as a whole did not, whether considered as an order or as individual radiations (Soligo and Martin, 2006).

islands away from mainland groups, small-bodied taxa will increase body size (with a tendency toward gigan-tism), and large-bodied taxa will decrease body size (with a tendency toward dwarfing). Evolution of body size on islands has been proposed to occur at a faster rate than in mainland counterparts (Millien, 2004). Evi-dence to support the island rule has mainly come from

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directed toward an optimal size when taking into primates (Leigh, 2001). It is important to note that allo-

account ecological strategies and body plan (Lomolino, metric relationships between body size and life history

(Ravosa, 1992, 1998, 2007; Ravosa et al., 1993; Ravosa and Daniel, 2010), variation in cranial form within and among papionin species (Leigh and Cheverud, 1991; Leigh, 2006), and interspecific cranial proportions among

explained as the result of ontogenetic scaling.

strictly on morphology is that this approach may ignore other factors driving the evolution of developmental pat-terns. When trying to interpret adult size variation, de-velopmental information not only of morphology but of underlying developmental systems can provide valuable insight because natural and sexual selection act not only

varying thresholds throughout life. Because of this, it remains a formidable challenge to discern how hormones are regulated to produce a given trait. Because of the relative ease of sample collection and measurement, cir-culating hormone levels have been used most often as indicators of endocrine status. Measurement of target tissue receptor density or location and identification of all components of various intracellular signaling cas-cades are approaches that are likely to yield more mean-ingful information regarding the relationship between hormones and phenotype; but, these kinds of studies are much more difficult to conduct.

Hormone levels have been hypothesized to affect trait evolution in two ways (Cox et al., 2009). The ‘‘evolution-

‘‘dwarfed’’ size (reviewed below).

The GH/IGF system

mulatta). However, these researchers did not find evi-dence of a splice variant of the GHR in rhesus tissue, similar to that found in the human, which is potentially responsible for the circulating high amounts of GHBP in humans (Ross et al., 1997). GH itself seems to have little effect on prenatal growth, and its effects on postnatal growth are largely mediated through IGF-I, IGF binding protein (IGFBP)-3, and the acid-labile subunit (ALS), which travels in a ternary complex with IGF-I and IGFBP-3. In addition to growth-promoting properties, GH acts in regulating lipid and carbohydrate metabolism (Rosenfeld and Hwa, 2009).

Insulin-like growth factor-I. The IGF ‘‘family’’ of growth factors includes insulin, IGF-I, and IGF-II. The IGFs share a large amount of sequence homology, and the structure of the IGFs and proinsulin are similar in structure, supporting the idea that the IGFs and insulin diverged from a common ancestral molecule. The struc-ture of IGF-I is highly conserved, demonstrated by cross-reactions generated by the serum of all mammals in a

(Murphy et al., 1987). More recently, gene knockout techniques have enabled evaluation of these models with mice by manipulating the levels of circulating IGF-I

ford, 2009). The regulation of IGF-I involves many fac-tors, including GH, estradiol, glucocorticoids, prolactin, parathyroid hormone, cyclic AMP, transforming growth

length, stature, and body mass (e.g., Liu and LeRoith, 1999). A brief review of the secretion and function of IGF-I during the human lifespan follows. In summary, IGF-I relates to size and growth rates both in fetal and postnatal life and plays an important role in the puber-tal growth spurt in conjunction with sex steroids.

factor-b, nutritional state, and insulin. Most circulating IGF is complexed with binding proteins (IGFBPs), which modulate ligand–receptor interaction on target cells. Depending on the particular protein (there are at least six IGFBPs), actions range from physical transportation and inactivation of IGFs to interaction with target cells and facilitation of the delivery of IGFs to their receptors. The majority of circulating IGF-I is complexed with

GH, but fetal insulin, under the regulation of fetal glu-cose availability. This pattern of fetal nutritional regula-tion of IGF-I is thought to persist until approximately 6 months postnatally (Yeung and Smyth, 2003). The fetal system is sensitive to maternal nutrition. Studies in sheep have shown that maternal nutrition can affect fe-tal and placental growth through IGF-I and IGFBP-3 expression (Osgerby et al., 2003). Experimental studies with rats suggest that maternal IGF-I affects fetal growth through the promotion of amino acid transfer through the placenta (Thongsong et al., 2002). Pregnant food-restricted rats have lower IGF-I levels associated with reduced weight gain and smaller fetal and placental sizes than those without food restriction (Monaco and

Yearbook of Physical Anthropology

At birth, cord serum levels of IGF-I show positive cor-relations with birth weight, placental weight, and gesta-tional age at birth regardless of the fact that female infants generally have higher levels of IGF-I than male infants (Geary et al., 2003). Premature infants show lower levels of IGF-I, IGFBP-3, and ALS in umbilical cord blood compared with infants born at term, and infants from preeclamptic pregnancies with low birth weight have associated low levels of IGF-I and IGFBP-3 (Diaz et al., 2002). Infants born large for gestational age have significantly higher IGF-I serum levels than infants average for gestational age (Christou et al., 2001). Simi-larly, infants SGA have significantly lower IGF-I levels than average for gestational age infants (Giuduce et al., 1995). In infancy, IGF-I levels decrease from birth up to 6 months of age and then rise again in later infancy. Recent research has uncovered a positive association between immediate postnatal growth velocity and IGF-I levels (Skalkidou et al., 2003).

levels of IGF-I in colostrum and breast milk, IGF-I levels tion (Bach, 1999).

in infant circulation, and infant growth rates and size (e.g., White et al., 1999). Dietary fat supplementation of lactating pigs resulted in increased levels of milk fat and IGF-I, which, in turn, was associated with enhanced suckling piglet growth rate (Averette et al., 1999). Sup-plementation of pregnant rhesus macaques with GH from the second trimester through 7 weeks postpartum

result of the earlier increases in GH. In children who were born at low birthweight, increases in IGF-I are associated with the period of ‘‘catch-up growth’’ (e.g., Leger et al., 1996). IGF-I levels are positively correlated with many different growth-related parameters in prepu-bertal children, including thigh muscle mass, oxygen uptake, and bone mass (e.g., Olney, 2003). The GH-IGF-I axis undergoes activation at the onset of puberty: the pulse amplitude of nocturnally secreted GH increases, and concentrations rise concurrent with onset of height

In postnatal life, IGFBP-3 levels change in a similar fashion but to a lesser degree than IGF-I. During pu-berty, researchers have noted an increase in the molar

in height velocity. ratio of IGF-I:IGFBP-3 and suggested that this may

et al., 1995). Increased GH secretion, and possibly an increased sensitivity to GH, is thought to be mainly re-sponsible for the pubertal increases in IGF-I, IGFBP-3, and ALS during this time. The increased mass and am-plitude of GH secretion in puberty is stimulated mainly by estrogens and aromatized androgens (e.g., Metzger and Kerrigan, 1994). These also have direct effects on IGF-I secretion. It is believed that there must be some other estrogen-dependent hypothalamopituitary mecha-nisms operating to sustain amplified GH secretion with concurrently elevated IGF-I levels in normal male and female puberty. At any other time, elevated IGF-I levels would feed back to suppress further GH release (Veld-huis, 1996).

GH/IGF axis in regulation of size: Nonhumans

poodles, finding support for IGF-I relating positively to lation.

size (Nap et al., 1993). Investigation of GH levels during development revealed that there was an initial increase in basal GH during early development that declined with age, whereas, in miniature poodles, basal GH levels began and stayed low (Nap et al., 1992). After this, Fav-ier et al. (2001) measured GH, IGF-I, and IGFII in Great Danes and beagles throughout development and found that, although both breeds had relatively elevated GH levels at very young ages, which then declined with age, the absolute levels were higher and sustained for a lon-ger period of time in Great Danes. However, no differ-ence in circulating IGF-I or IGF-II was found between the two breeds. Recent genetic research in domestic dogs has identified a single nucleotide polymorphism of the IGF1 gene that is ubiquitous to all small breeds and absent from giant breeds (Sutter et al., 2007). This is strong evidence indicating that this gene and its prod-ucts play a major role in determining body size in small domestic dogs; furthermore, the authors note that the sequence variants likely predate the estimated time of domestication, allowing for extremely rapid diversity in size when breeds were established. Taken together, this body of research suggests that in an environment of strong selection pressures (in this case, artificial selec-tion—whether directly on size or on some other behav-ioral or morphological phenotype that causes a corre-lated change in size), where diversity in both size and shape has occurred very rapidly, there may be a number of different hormonal ‘‘pathways’’ for reaching larger or

Nonhuman primates: Single-species studies. Consid-erable detail concerning the hormonal regulation of growth and size in rhesus macaques (M. mulatta) has been established through a series of experiments involv-ing administration of IGF-I and estradiol to female rhe-sus macaques. Some of the earliest work in this area establishes that gonadal status (intact vs. not intact) influences changes in body weight in association with IGF-I (Wilson et al., 1984). Estradiol was shown to have a direct effect on IGF-I secretion independent of GH (Wilson, 1986). A comparison of the tempo of hormonal and skeletal maturation among groups of female rhesus housed indoors and outdoors demonstrates that those individuals housed outdoors show a distinct seasonal rhythm in secretion of GH and IGF-I, in contrast to those housed indoors (Wilson et al., 1988). As a conse-quence of this, together with delayed reproductive matu-ration in females housed outdoors, skeletal maturity of females housed indoors is significantly advanced. Other experiments show that administration of IGF-I inhibits further GH release but still stimulates growth in crown-rump length (Wilson, 1997). These experiments are im-portant and have generated a large amount of informa-tion regarding the operation of mechanisms that regu-late puberty and growth in M. mulatta. However, the ex-

information was obtained makes it difficult to apply to evolutionary explanations of variation in growth and size. Specifically, it is unclear whether the responses shown by an animal’s physiology to administration of ex-ogenous hormones are similar to what would result from endogenous rises in hormone levels. Such techniques can, through this type of manipulation, define the boun-daries for age-related effects of hormones, but cannot

Nonhuman primates: Comparative studies. Follow-ing on the groundwork laid by the studies described above, a recent article explored the relationship between adult size and levels of IGF-I, IGFBP-3, and GHBP in 11 papionin species (Bernstein et al., 2007). In particular, the goal of this research was to assess whether larger-bodied papionins have higher levels of growth-related

HOW BODY SIZE EVOLVES 53

wileyonlinelibrary.com.]

both share high levels of IGF-I, and Papio, Theropithe-cus, and Lophocebus share lower levels.

Yearbook of Physical Anthropology

54 R.M. BERNSTEIN

The existence of human pygmy populations in multiple areas across the world suggests that this phenotype has

reproduction, increased stress resistance, and longer life evolved in parallel multiple times and perhaps in

human populations show mutations in the IGF-I recep- tropical rainforest environments (e.g., Cavalli-Sforza,

tor gene that confers reduced activity of the IGF-I recep- 1986; Diamond, 1991). These include predictions regard-

A detailed study on the growth allometry of Efe pyg-mies found that size differences both between male and female pygmies, and among pygmies and nonpygmies,

et al., 2002). could largely be explained by ontogenetic scaling (Shea

Earlier investigations into the physiological underpin-nings of pygmy body size have touched both on circulat-ing hormone levels and in cell responsiveness to growth-related hormones. Testing the response of pygmy IGF-I secretion to exogenous GH administration demonstrated that the failure to elicit a normal increase in IGF-I in the majority of individuals tested was most similar to what occurs in people with a dwarfed, low-IGF-I phenotype (Merimee et al., 1982). Measuring serum levels of IGF-I in Efe pygmies, Merimee et al. (1987) found that levels were blunted mainly during adolescence, and that the ad-olescent growth spurt was similarly depressed. No signif-icant differences in IGF-I levels were found before pu-berty, and no differences in IGF-II or testosterone were

HOW BODY SIZE EVOLVES 55

More recently, a study of Baka pygmies, compared with Bantu, showed a highly significant decrease (eight-fold) in GHR gene expression that was not associated with any sequence variation of the GHR gene (Bozzola et al., 2009). As in most other studies of circulating hor-mone levels in pygmies, serum hormone levels were reduced in the Baka compared with the Bantu (GHBP more so than IGF-I, however). One of the major draw-backs of several of these studies is that, given their opportunistic nature, sampling often centers on adults or individuals in the latter part of adolescence.

Recent work links the pygmy growth pattern to a life history strategy that maximizes reproductive fitness in a high-mortality environment. Researchers looking into the cause of small stature in human pygmy populations have suggested that a relatively early onset of reproduc-tive maturation is the key to understanding this pheno-type (Migliano et al., 2007). Specifically, the shift to ear-lier female fitness peaks relative to those in nonpygmy populations is explained by high mortality rates and lim-ited resource availability (e.g., Charnov and Berrigan, 1993). Importantly, the authors emphasize that short stature is a by-product of selection for earlier matura-tion, rather than being the target of selection itself. In this case, one would not necessarily expect that levels of growth-related hormones during ontogeny would differ between pygmy populations and nonpygmy populations; rather, one might see modifications of the temporal expression of the GH/IGF axis as a secondary effect of earlier activation of the hypothalamic–pituitary–gonadal

Stearns (1992) defines tradeoffs as fitness costs that occur when a beneficial change in one trait is linked to a detrimental change in another and as linkages between traits that constrain the simultaneous evolution of two or more traits. Hormones initiate the transfer of resour-ces from somatic functions to reproductive functions when they mobilize an organism for reproduction and

56 R.M. BERNSTEIN

effects to subsequent generations can occur in the pres-ence or absence of modifications to the germ line. In intrauterine life, hormones affect phenotype in a variety of ways, including effects on placental morphology, struc-ture and modification of synthesis and metabolism of hormones, and direct effects on tissues. In these roles, they shape intrauterine development in response to envi-ronmental conditions; in effect, they produce an epige-nome representative of conditions during development (Fowden and Forhead, 2009, p 619).

through postnatal life (Kappeler et al., 2009).

(Kaati et al., 2007).

The Dutch Hunger Winter Families Study tracks the later-life effects of an adverse in utero environment in

sity scenarios, and a consequence of size-specific mortal-ity. Given the preceding discussion on the prenatal (through placental/maternal hormone levels) and early life epigenetic effects (via dietarily influenced endoge-nous hormone production and sensitivity) on metabolism and growth, it seems fitting to add the insulin/IGF path-ways as a mechanistic link between the manifestations of growth and size variation in response to environmen-tal influences (Fig. 6).

HOW BODY SIZE EVOLVES 57

This review has focused on some components of one of the more important hormonal networks involved in determining adult size. The GH/IGF system plays a key role in growth, metabolism, reproduction, and senes-cence, from nematodes to humans. According to the evo-lutionary constraint and evolutionary potential hypothe-ses of hormone action, hormones can affect trait evolu-tion through modification of circulating hormone levels or through alteration in tissue responsiveness. The small

portion of the literature dealing with the GH/IGF system and size reviewed here clearly show that both are impor-tant. Specifically, circulating levels of IGF-I vary with size across a number of taxa, and receptor sensitivity also affects size.

instead be more important for explaining how size varia-tion evolved (Bernstein et al., 2007).

Although this review focused on particular aspects of one hormonal system, it is of course true that size differ-ences are not generated by modifications to the GH/IGF axis alone. There are myriad other hormones involved in the processes of growth, maturation, and attainment of final adult size. Glucocorticoids and sex steroids, in par-ticular, exert potent effects on size both prenatally and postnatally. Sex steroids play a critical role during fetal and early neonatal development in the determination of specific gender-related patterns of spontaneous GH pro-files. In particular, linear skeletal growth, body weight, and organ size exhibit a strong dependence on either a pulsatile or continuous (‘‘male’’ or ‘‘female’’) temporal mode of GH release, which are, in turn, related to higher and lower somatic growth rates, respectively. These dif-ferential temporal patterns of GH delivery to target tis-sues can markedly influence tissue responses at the level of specific gene expression and protein production. In the generation of size variation, estrogens are particularly important because they act to promote closure of long bone epiphyses and, therefore, place limits on overall measures of length or stature.

ACKNOWLEDGMENTS

The author thanks B. Shea for discussions on hor-mones and body size and B. Richmond for encourage-ment and feedback during the writing process. She is grateful to Bob Sussman and three anonymous reviewers for their comments and suggestions on an earlier version of this manuscript. She is always thankful for support from Jared, Sylvia, and Vivian, who make all things possible.

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